The objective of the proposed study is to understand the thymic and peripheral mechanisms responsible for establishing T cell tolerance to self antigens. Failure of these mechanisms results in autoimmunity. Thus, the knowledge gained from these studies will provide important insight into the causes and possible therapies for autoimmune diseases. Moreover, understanding the mechanisms of peripheral tolerance may provide a theoretical basis for antigen-specific suppression of the. immune response which may be desirable clinically, for example, to prevent graft rejection. The experimental system is a transgenic mouse in which virtually all T cells are potentially autoreactive to an endogenously-expressed self antigen. Thymic mechanisms of tolerance physically eliminate some of these cells early in their development, before they become fully reactive. However, many of the cells complete their maturation and escape into the periphery. Despite the fact that potentially autoreactive cells constitute a significant percentage of the peripheral CD4+ T cells, the mouse is not autoreactive because peripheral mechanisms of tolerance prevent the cells from responding. The predominant mechanism of peripheral tolerance in these transgenic mice is anergy, defined as the functional inactivation of T cells upon encounter with self antigen that renders them subsequently non-responsive. Anergy as a mechanism of peripheral tolerance will be examined and the potential of these cells to become autoreactive will be assessed. Specifically, anergic cells will be characterized phenotypically and functionally in vitro and in vivo. The factors that determine whether a given clone is tolerized by deletion or anergy will be examined. The structural characteristics of T cell receptors that recognize the self antigen will be defined.